Tristetraprolin Inhibits Poly(A)-Tail Synthesis in Nuclear mRNA that Contains AU-Rich Elements by Interacting with Poly(A)-Binding Protein Nuclear 1
Tristetraprolin Inhibits Poly(A)-Tail Synthesis in Nuclear mRNA that Contains AU-Rich Elements by Interacting with Poly(A)-Binding Protein Nuclear 1
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Tristetraprolin 通过与 Poly(A) 结合蛋白 Nuclear 1 相互作用，抑制含有富含 AU 元素的核 mRNA 中的 Poly(A) 尾合成
作者：
Yu;Shun;P. Chiang;Nien;Yu;G. Chang;Ching
Tristetraprolin结合mRNA富含AU的元件，从而促进胞质溶胶中成熟mRNA的不稳定。方法学/主要发现为了理解tristetraprolin如何在机制上发挥作用，我们用噬菌体展示文库对与tristetraprolin相互作用的蛋白质进行生物淘选，并检索了多聚腺苷酸结合蛋白核1的片段，该片段通过结合未成熟的多聚腺苷酸尾来帮助mRNA的3 '-聚腺苷酸化，从而增加多聚腺苷酸聚合酶的活性，其直接负责多聚腺苷酸化。在下拉和免疫共沉淀试验中，使用三曲脯氨酸和多聚腺苷酸结合蛋白核1缺失突变体表征三曲脯氨酸/多聚腺苷酸结合蛋白核1相互作用。Tristetraprolin通过其串联锌指结构域和另一个区域与poly（A）结合蛋白核1的羧基端区域相互作用。虽然tristetraprolin和poly（A）-结合蛋白核1位于细胞质和细胞核，它们在体内相互作用，只有在细胞核。在体外，tristetraprolin结合poly（A）结合蛋白核1和poly（A）聚合酶，从而抑制编码肿瘤坏死因子α、GM-CSF和白细胞介素-10的含AU富集元素mRNA的聚腺苷酸化。串联锌指结构域缺失的tristetraprolin突变体是一种不太有效的抑制剂。限制于细胞核的tristetraprolin突变体的表达导致含AU富集元件的肿瘤坏死因子α/荧光素酶mRNA构建体的下调。除了已知的胞质mRNA降解功能外，tristetraprolin还通过与细胞核中的poly（A）结合蛋白nuclear 1相互作用来抑制poly（A）尾的合成，从而调节富含AU元素的mRNA的表达。
Background Tristetraprolin binds mRNA AU-rich elements and thereby facilitates the destabilization of mature mRNA in the cytosol. Methodology/Principal Findings To understand how tristetraprolin mechanistically functions, we biopanned with a phage-display library for proteins that interact with tristetraprolin and retrieved, among others, a fragment of poly(A)-binding protein nuclear 1, which assists in the 3'-polyadenylation of mRNA by binding to immature poly(A) tails and thereby increases the activity of poly(A) polymerase, which is directly responsible for polyadenylation. The tristetraprolin/poly(A)-binding protein nuclear 1 interaction was characterized using tristetraprolin and poly(A)-binding protein nuclear 1 deletion mutants in pull-down and co-immunoprecipitation assays. Tristetraprolin interacted with the carboxyl-terminal region of poly(A)-binding protein nuclear 1 via its tandem zinc finger domain and another region. Although tristetraprolin and poly(A)-binding protein nuclear 1 are located in both the cytoplasm and the nucleus, they interacted in vivo in only the nucleus. In vitro, tristetraprolin bound both poly(A)-binding protein nuclear 1 and poly(A) polymerase and thereby inhibited polyadenylation of AU-rich element–containing mRNAs encoding tumor necrosis factor α, GM-CSF, and interleukin-10. A tandem zinc finger domain–deleted tristetraprolin mutant was a less effective inhibitor. Expression of a tristetraprolin mutant restricted to the nucleus resulted in downregulation of an AU-rich element–containing tumor necrosis factor α/luciferase mRNA construct. Conclusion/Significance In addition to its known cytosolic mRNA–degrading function, tristetraprolin inhibits poly(A) tail synthesis by interacting with poly(A)-binding protein nuclear 1 in the nucleus to regulate expression of AU-rich element–containing mRNA.
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影响因子：
10.5
作者：
Sato, Hanae;Maquat, Lynne E.
通讯作者：
Maquat, Lynne E.
DOI：
--
发表时间：
1990-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Raymond N. DuBois;Michael W. McLaneS;Kevin RyderQ;Lester F. Laull;D. Nathans
通讯作者：
Raymond N. DuBois;Michael W. McLaneS;Kevin RyderQ;Lester F. Laull;D. Nathans
影响因子：
--
作者：
Gregory A. Taylor;Michael J. Thompson;W. Lai;P. Blackshear
通讯作者：
Gregory A. Taylor;Michael J. Thompson;W. Lai;P. Blackshear
影响因子：
14.9
作者：
Sandler H;Kreth J;Timmers HT;Stoecklin G
通讯作者：
Stoecklin G
DOI：
10.1101/gr.4.6.317
发表时间：
1995-06
期刊：
PCR methods and applications
影响因子：
--
作者：
F. Salles;S. Strickland
通讯作者：
F. Salles;S. Strickland